Recent studies have demonstrated that the functional messenger RNA of eukaryotic cells and of most viruses contains adenylate residues in its 3'-position. An enzyme that can synthesize poly(A) has been characterized in calf thymus nuclei. A related enzyme has been reported in the extra-mitochondrial cytoplasmic fraction of some cells. Most of these enzymes generally add one adenylic acid moiety to pre-existing RNA, usually tRNA and hence they are not true polymerizing enzymes. We have recently reported that rat liver mitochondria contain a very active enzyme that can polymerize several adenylate residues to form poly(A). In several aspects, this enzyme differs from the mitochondrial DNA-dependent RNA polymerase. We have also shown that the activity or level of this enzyme is relatively low in some hepatomas. The broad objectives of this research program are (a) to purify poly(A) polymerase from the mitochondria of normal and neoplastic tissues, (b) to study the properties of the purified enzymes, (c) to determine their subunit compositions, (d) to investigate the physiological regulation of this enzyme, (e) to establish that low mitochondrial poly(A) polymerase activity is a characteristic property of cancer cells, and if so, (f) to examine the factor or factors that are responsible for the relative lack of enzyme activity in tumors. Preliminary experiments have suggested that tumor enzymes are insensitive to a rifamycin analogue, suggesting a structural difference between normal and malignant enzymes. A variety of rifamycin analogues and other drugs will be screened in an attempt to find a drug or drugs that can selectively inhibit tumor poly(A) polymerase.